Squamous cell cancer of the head and neck (SCCHN) is locally invasive, and frequently spreads to the cervical lymph nodes. Locally advanced disease is treated with radiotherapy plus chemotherapy and/or cetuximab (an anti-EGF receptor antibody), but the cure rate is less than 40% and toxicities are severe. The overall goal of this SBIR grant proposal is to enhance the outcomes of therapy for patients with locally advanced or relapsed SCCHN without increasing treatment related toxicity. MV-NIS is an improved oncolytic measles virus that has been engineered to code for the thyroidal sodium iodide symporter (NIS), is amenable to noninvasive monitoring by radioiodine imaging and has antitumor activity in the FaDu mouse xenograft model of human SCCHN. MV-NIS has been administered safely to human subjects but never by direct intratumoral injection. In light of its demonstrated safety, its activity in preclinical SCCHN models, and its potential compatibility with chemoradiotherapy, we now hypothesize that MV-NIS can significantly enhance the outcomes of therapy for SCCHN when correctly incorporated into existing treatment programs for locally advanced disease. Specific aims are as follows: Phase I SBIR Aim 1. To evaluate the impact of humoral immunity on the antitumor activity of MV-NIS, given as direct intratumoral injection, in mice with human SCCHN xenografts. Phase II SBIR Aim 2. To conduct a phase I clinical trial of single agent MV-NIS, administered by intratumoral inoculation, in patients with relapsed SCCHN. Aim 3. To determine whether established treatment modalities for SCCHN are compatible with intratumoral MV-NIS in preclinical models. Upon completion of this work, NISCO will be ready to combine MV-NIS with conventional SCCHN frontline therapy in a phase II clinical trial in patients with locally advanced disease. This will be the precursor of a pivotal phase II/III study to prove the utility of MV-NIS in the treatment of locally advanced SCCHN. PUBLIC HEALTH RELEVANCE: Oncolytic virotherapy is a promising new approach to the treatment of cancer, but its development has been hindered by the lack of available technologies for non-invasively monitoring the spread and elimination of the virus infection in a treated patient. NISCO has acquired an oncolytic measles virus (MV-NIS) that has been engineered to facilitate the application of non-invasive imaging technologies to monitor its spread. Based on the observation that MV-NIS is effective in a preclinical model of head and neck cancer, NISCO now proposes to advance the virus to clinical testing in poor prognosis patients with this form of cancer. The expectation is that the new virus will prove effective therapy for head and neck cancer and that non-invasive monitoring of viral spread will allow us to optimize dosing, scheduling, and synergistic interactions with conventional head and neck cancer treatments.